Genetic–pathologic characterization of myeloproliferative neoplasms

Abstract

Myeloproliferative neoplasms (MPNs) are clonal hematopoietic stem cell disorders characterized by the proliferation of one or more myeloid lineages. The current study demonstrates that three driver mutations were detected in 82.6% of 407 MPNs with a mutation distribution of JAK2 in 275 (67.6%), CALR in 55 (13.5%) and MPL in 6 (1.5%). The mutations were mutually exclusive in principle except in one patient with both CALR and MPL mutations. The driver mutation directed the pathologic features of MPNs, including lineage hyperplasia, laboratory findings and clinical presentation. JAK2-mutated MPN showed erythroid, granulocytic and/or megakaryocytic hyperplasia whereas CALR- and MPL-mutated MPNs displayed granulocytic and/or megakaryocytic hyperplasia. The lineage hyperplasia was closely associated with a higher mutant allele burden and peripheral cytosis. These findings corroborated that the lineage hyperplasia consisted of clonal proliferation of each hematopoietic lineage acquiring driver mutations. Our study has also demonstrated that bone marrow (BM) fibrosis was associated with disease progression. Patients with overt fibrosis (grade ⩾2) presented an increased mutant allele burden (P<0.001), an increase in chromosomal abnormalities (P<0.001) and a poor prognosis (P<0.001). Moreover, among patients with overt fibrosis, all patients with wild-type JAK2/CALR/MPL (triple-negative) showed genomic alterations by genome-wide microarray study and revealed the poorest overall survival, followed by JAK2-mutated MPNs. The genetic–pathologic characteristics provided the information for understanding disease pathogenesis and the progression of MPNs. The prognostic significance of the driver mutation and BM fibrosis suggests the necessity of a prospective therapeutic strategy to improve the clinical outcome.

Bone Marrow Histology Characteristics in MPL515 Mutated Thrombocythemia with Various Degrees of Myelofibrosis: A Cross Sectional Follow-up Study in Eight Cases

“…The frequency of the MPLW515L/K mutation in the original studies were 5.3% in the JAK2V617F wild type (WT) ET and 9.6% in JAK2V617F wild type PMF patients [4,5]. The rare occurrence rate of the MPLW515L/K mutations have been confirmed in two recent studies within large groups of WHO defined MPN population and JAK2 WT ET and MF population [6][7][8][9]. The Italian GIMEMA cross sectional study subdivided 952 ET patients into 546 JAK2V617F mutated (57%) and 418 JAK2 wild type (43%) and found 30 cases (3% of total ET and 7.2% of JAK2 wild type ET) carrying the MPLW515WL/K mutation.…”

“…In 2006, two novel MPL515 somatic mutations (MPLW515L and MPLW515K) have been discovered in 5% and 1% in large cohorts of acquired ET and Myelofibrosis (MF) patients respectively [4,5]. Within one center cohort of 402 MPN patients in Seoul there were 3 cases of ET and 3 cases of myelofibrosis (MF) patients (N=6, 1.7% of 402, cases 2 to 7, Table 1) who carry an acquired gain of function mutation of the MPL receptor as the cause of ET or MF [6]. MPN515 case 1 is the first one found in our cohort of ET patients seen by the MPN study group in Rotterdam Antwerp and Brussels, who carry an acquired gain of function mutation of the MPL receptor as the cause of ET.…”

Bone marrow histology in CALR mutated thrombocythemia and myelofibrosis: results from two cross sectional studies in 70 newly diagnosed JAK2/MPL wild type thrombocythemia patients

“…The reticulin iber content and pattern of iber density in each patient at time of irst diagnosis and in subsequent trephine biopsies is of utmost prognostic importance [9,10,14,15]. Bone marrow ibrosis (myelo ibrosis = MF) is a secondary to the myeloproliferative transformation of bone marrow hematopoiesis in clonal JAK2 V617F mutated ET and PV, MPL 515 mutated ET and CALR ET / PMGM characteristics without features of PV ( Figure 2) [9,30,31]. Myelo ibrosis (MF) is according to Table 2 [14,15].…”

“…The blood and bone marrow features have been explicitly described in great detail by the ECP and ECMP classi ications between 2005 and 2017 for the each of the JAK2 V617F mutated ET and PV and MPL 515 and for CALR mutated pre ibrotic thrombocythemia and myelo ibrosis ( Table 2) [16][17][18][19][20][21][22][23][24][25][26]. Each of the MPDs JAK2 V617F , MPL 515 and CALR mutated ET, PV and PMGM as well as Ph + ET and Ph + CML are associated with various degrees of myeloid metaplasia of the spleen and secondary myelo ibrosis [9,30,31].…”

Unique Case of Myeloproliferative Neoplasm with Two Rare Clonal Abnormalities: Rare <b><i>JAK2</i></b> Exon 12<b><i></i></b> Mutation and Rare e14a3 (b3a3) BCR/ABL Fusion Transcript

“…At protein level, it predicted replacement of amino acid residues 540 to 543 (IRNE) with a dipeptide (MK) resulting in a net loss of 2 amino acids (p.I540_E543delinsMK). So far, only 2 cases with this specific exon 12 mutation in JAK2 have been reported in the literature [7, 8]. The patient continued to remain stable with sporadic need for phlebotomy and did not return for 3 years.…”